Screening Potential Pregnane X Receptor Activators of Host and Microbial Origin
Open Access
- Author:
- Cole, Darnella
- Graduate Program:
- Pathobiology
- Degree:
- Master of Science
- Document Type:
- Master Thesis
- Date of Defense:
- April 04, 2024
- Committee Members:
- Andrew Patterson, Thesis Advisor/Co-Advisor
John Patrick Vanden Heuvel, Committee Member
Anthony Schmitt, Professor in Charge/Director of Graduate Studies - Keywords:
- PXR
Microbiome
Biotransformations
Metabolites
Rifampicin - Abstract:
- The microbiome comprises a complex community of microorganisms crucial for human existence. With their population reaching trillions, these microorganisms are pivotal for human health and the maintenance of overall physiology. The gut microbiota plays an important role in maintaining systemic homeostasis through the metabolism of endogenous compounds, natural products, and xenobiotics. Many of these metabolites from gut microbiota metabolic processes exert their physiological effects by binding to transcription factors, thereby influencing the expression of genes crucial for metabolism, with one example being the pregnane X receptor (PXR). Given the multitude and diverse array of metabolites generated, metabolized, and/or modified by the gut microbiota, it is vital to understand how these compounds interact with the body. PXR holds significance in regulating the expression of genes and their encoded proteins that are crucial for host metabolism including xenobiotic metabolism. To delve deeper into the impact of gut microbiota impact on the expression of genes essential for host metabolism, we conducted a library screen of 200 metabolites originating from microbial sources to assess their ability to activate PXR. Following the assessment of each microbial metabolite's capacity to activate PXR at a standardized concentration, the most potent metabolites were identified. These were subsequently employed in a dose-response analysis to ascertain the extent of PXR activation across varying concentrations. Our findings reinforce the notion of the significant role of the microbiome in human physiology, particularly in the metabolism of xenobiotic substances.